The progression of primary cancer to metastases is an ominous event in patients at primary diagnosis, and is an important cause of morbidity and mortality. Presently used targeted therapies for metastatic disease such as herceptin/trastuzumab (the humanized therapeutic antibody against ErbB-2/Her-2 receptor) combined with chemotherapy have demonstrated modest improvement over more traditional therapies. This has also been observed for other metastatic diseases such as colorectal, melanoma, pancreatic, and kidney. Therefore, there is a need to develop treatment that selectively targets rate-limiting signaling driving the early process of cancer cell invasion.
An early event by which cancer cells acquire autonomous motile properties is driven by focal adhesion (FA) signaling, which is essential for cell-substrate generating forces needed for the coordination of the entire process of cancer cell migration and invasion. Central to FA signaling is the focal adhesion kinase (FAK) and its homologue Pyk2, two kinases activated by integrins and a number of growth factors receptors, including ErbB-2/Her2 receptor. These proteins also serve as scaffolding proteins that mediate multiple protein-protein interactions critical for cancer cell invasion, e.g. cell survival, anoikis (programmed cell death induced by cell detachment from the extracellular matrix, which is probably regulated by PI3K signaling), angiogenesis, and survival of invasive cells in new environments. For instance, the non-catalytic domains of FAK contain binding motifs for Src kinases and interact with other partners, including PI3K, Crk, PLCλ, p130Cas, Grb7, and paxillin; these interactions represent the core of FA signaling. Members of this network, including FAK, PKCα and Akt-1 are hyperactivated in some invasive cancers, and their inhibition using genetic approaches, e.g. RNA interference, or chemical inhibitors reduced metastasis formation. However, approaches targeting these proteins individually have proven of limited efficacy due in part to compensatory signaling loops that can overcome a single target inhibition. As such, the field of drug discovery is moving towards a multitargeting approach to target multifactorial diseases such as cancer.
Pyrimidine and pyridinone derivatives have been reported to inhibit focal adhesion kinase (FAK) and its homologue Pyk2, two FA signaling proteins, or FAK and IGFR-1R receptor. Nonetheless, results for some of these agents have revealed only modest disease stabilization thus far.